Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 1 Efficacy of Leflunomide Compared to Methotrexate in the Treatment of Moderate to Severe Plaques Psoriasis: A Randomized Controlled Clinical Trial Hany Othman Aboelwafa1, Hassan Abou Khodair Mohamed1, Doaa Mamdouh Ibrahim2, Nermeen Ibrahim Bedair3 1 Department of Dermatology, Venereology and Andrology, AlAzhar University- Damietta Faculty of Medicine, Damietta, Egypt 2 Elhusseinya Central Hospital, Ministry of Health, Egypt 3 Department of Dermatology, Andrology, Sexual Medicine and STDs, Faculty of Medicine, Helwan University, Cairo, Egypt Key words: psoriasis, PASI, methotrexate, leflunomide Citation: Aboelwafa HO, Abou Khodair Mohamed H, Ibrahim DM, Bedair NI. Efficacy of Leflunomide Compared to Methotrexate in the Treatment of Moderate to Severe Plaques Psoriasis: A Randomized Controlled Clinical Trial. Dermatol Pract Concept. 2024;14(3):e2024165. DOI: https://doi.org/10.5826/dpc.1403a165 Accepted: February 25, 2024; Published: July 2024 Copyright: ©2024 Abo Elwafa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Hany Othman Abo Elwafa, Department of Dermatology, Venereology and Andrology, Damietta Faculty of Medicine, Damietta, Egypt. Email: drhanyaboelwafa@gmail.com Introduction: Psoriasis is a chronic inflammatory autoimmune skin disease. Several treatment options are available including topical and systemic options. Methotrexate was the main systemic medication in treating severe psoriasis, yet adverse events can limit its use. Leflunomide is an isoxazole derivative that inhibits the synthesis of pyrimidines, and subsequently inhibits RNA and DNA synthesis. Objectives: As available data directly comparing MTX to leflunomide in psoriasis are lacking, this double blinded study was designed to compare the efficacy of methotrexate versus leflunomide in the treatment of moderate to severe psoriasis. Methods: The study included 40 patients (25 males and 15 females) with chronic plaque psoriasis. s. Patients were randomly assigned to one of two equal groups, group A for subcutaneous methotrexate injections and group B for leflunomide (loading dose 100mg daily for the first 3 days, then 20 mg daily for 3 months. Disease severity was determined by psoriasis area and severity index (PASI) score before and at the end of treatment The treatment response was evaluated at the baseline and weeks 4, 8 and 12 PASI score. Results: Both groups were matching at the baseline in aspects of gender, age, disease duration and PASI scores Both medications yielded comparable results with no significant difference between both groups in PASI score neither in side effects. Conclusions: Leflunomide can be as effective as methotrexate in treatment of moderate to severe psoriasis ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 Introduction Psoriasis is a chronic proliferative and inflammatory skin disease. Clinically, the disease is characterized by erythema- tous plaques covered by silvery scales mainly on the extensor surfaces, scalp, and lumbosacral region. Joints and eyes can be affected. Several types are described, but the plaque type is the commonest [1,2]. Disease affects 0.2% to 4.8% of the population. It is of unknown etiology. However, it is con- sidered an autoimmune disease mediated by T lymphocytes, with genetic predisposition as it runs in families. Any skin injury (eg mechanical, chemical, radiation) seems to induce the psoriatic lesions. Additionally, the disease is worsened by certain drugs (eg chloroquine, lithium, and beta-blockers). But it improved in summer. Other triggering factors include infections, stress, smoking, obesity, alcoholism, and hypogly- cemia [3]. The main pathophysiological changes include stimulating keratinocyte proliferation by infiltration of the skin by acti- vated T-cells, with subsequent formation of thick plaques. Other features include epidermal hyperplasia and parakera- tosis. The epidermal cells also fail to secrete lipids which re- sults in flaky and scaly skin, which is typical of psoriasis [4]. Psoriasis can present with different morphological patterns (eg plaque, guttate, rupioid, erythrodermic, pustular, inverse, elephantine, and psoriatic arthritis) [5,6]. The Psoriasis Area Severity Index (PASI) is the most widely used assessment tool to estimate the severity of the condition and permits treatment evaluation. Topical therapy is used for mild to moderate psoriasis (eg coal tar, dithranol, corticosteroids, vitamin D analog, and retinoids) [7]. Systemic drugs are used in severe cases. Methotrexate, retinoids, cyclosporine, and fumarates are possible treat- ment options. Routine blood, liver and renal functions should be assessed in patients during systemic therapy. Bi- ological agents (eg infliximab, adalimumab, etanercept, and interleukin antagonists) work by interrupting the immune process. However, there is a serious risk of infections in these patients (on biological treatment) and all precautions should be taken to prevent severe immunosuppression in such pa- tients [8,9]. Methotrexate (MTX) is a folate antagonist initially used to treat hematological malignancies. It has been used as an anti-inflammatory drug in psoriasis for more than 50 years. It is the first-line systemic treatment agent in the United States and Europe. It is used for moderate-to severe psori- asis when topical treatments are ineffective, impractical, or contraindicated [10]. It was suggested to exert its action by its antiproliferative effects, increasing susceptibility of T-lymphocytes and monocytes to the inhibition of the purine and pyrimidine synthesis, anti-inflammatory and immuno- suppressant effects [11,12]. Leflunomide is an isoxazole derivative. It is primarily in- hibiting the dihydro-orotate dehydrogenase, a key enzyme in the de novo synthesis of pyrimidines, and subsequently inhibit RNA and DNA synthesis. Activated T-lymphocytes may be especially susceptible to leflunomide. It also has im- munomodulatory and anti-inflammatory effects [13]. Le- flunomide is a useful and well tolerated treatment option for plaque psoriasis. It has some advantages over MTX in the treatment of psoriasis (eg it is well tolerated, convenient and effective). In addition, orally administered leflunomide is cost effective. Since biologics are costly and not easily avail- able, leflunomide may be one of the alternative treatment options of plaque type of psoriasis [14,15]. Objectives As available data directly comparing MTX to leflunomide in psoriasis are lacking, this double blinded study was designed to compare the efficacy of methotrexate versus leflunomide in the treatment of moderate to severe psoriasis. Methods Recruitment of Participants This comparative clinical study included 40 patients with chronic plaque psoriasis that were diagnosed clinically. Patients were recruited from the Dermatology outpatient clinic of Al-AzharUniversity Hospital (New Damietta) be- tween October 2022 and September 2023. The study was approved by the Research Ethical Committee, Damietta Faculty of Medicine, Al-Azhar University (IRB 00012367- 22-06-002), and fulfilled all the ethical aspects required in human research. All patients received full information about both medications used, the study design and all the possi- ble side effects. All recruits provided an informed consent to participate in the study. We excluded patients younger than 18 years or older than 60, pregnant and lactating women, patients with any autoimmune disease (eg rheumatoid arthri- tis, systemic lupus) patients with any dermatological disease other than psoriasis, patients with hematologic disorders (eg thrombocytopenia, anemia), patients with systemic chronic diseases (eg liver, kidney or heart diseases), patients who received systemic anti-psoriatic treatment for the last 3  months before inclusion in the study and those receiv- ing any topical treatment for 4 weeks prior to enrollment. Patients with history of allergy to any of the medications used were also excluded. Randomization and Assigning Treatment Groups Patients were randomly assigned to one of the two groups us- ing closed envelop technique. Group A included 20 patients Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 3 who received subcutaneous methotrexate injection treat- ment once per week for 3 months. Group B of 20 patients who received oral leflunomide regimen loading dose 100 mg daily for the first 3 days then 20 mg daily for 3 months. Ran- domization was performed by generation of random num- bers by computer and each number indicate one treatment and sealed in an enclosed envelope which opened before starting treatment by a nurse who was blinded to the other parts of the study. All patients were subjected to full history taking, thor- ough general and dermatological examination. The disease severity as well as treatment response were determined by (PASI) score at the baseline and at weeks 4, 8 and 12. The documentation of the lesion was performed using digital photography (using iPhone 12 camera) at the baseline and week 12. The laboratory investigations were performed at the baseline and at 4, 8 and 12 weeks after treatment. These included complete blood picture (CBC), liver and kidney function tests. In the methotrexate group, all patients re- ceived folic acid 5mg daily except on the day of injection. Every patient received a printed checklist of the possible side effects of the treatment and was instructed to report any of the mentioned manifestations on every visit. The mani- festations included in the checklist were nausea, vomiting, diarrhea, abdominal pain, dyspepsia, headache, dizziness, asthenia, back pain, any skin rash, pruritus and alopecia. Statistical Analysis The statistical package for social science (SPSS), version 20 (IBM® SPSS® Inc.) was used to perform all analysis. The data were originally anonymized by coding and fed to the personal computer. Categorical variables were summarized by their relative frequency and percentages. However, the quantitative variables were represented by the arithmetic mean and standard deviation (SD), minimum and maximum when appropriate. Groups were compared by Student T test when quantitative and compared by Pearson chi-square or Fisher exact test (when appropriate). P value ≤ 0.05 was con- sidered statistically significant, at confidence intervals (CI) of 95.0%. Results Forty patients completed the study and were included in the analysis. Demographic and clinical characteristics of the studied patients are listed in Table 1. Both groups showed matching characteristics in aspects of gender, age, disease du- ration and presence of positive family history. Among the methotrexate group (Figures 1-3); the mean PASI score at the baseline was 33 ± 11.68, by the end of the fourth week it improved to 14.66 ± 7.35 and at the end of the study at week 12 it improved to 1.95 ± 1.33. While among the leflunamide group (Figures 4-8); the mean PASI score at the baseline was 31.75 ± 7.71 and improved at the end of the 4th week to 17.46 and by the end of the study at week 12 to 1.94 ± 1.28. Both groups showed compara- ble improvement at all the 3 visits (P = 0.693, 0.141, 0.99, respectively). The laboratory investigations after 12 weeks of treatment were comparable between both methotrexate and lefluno- mide groups, except for significant increase in red blood cell count, hemoglobin concentrations, and total protein in the methotrexate group, while albumin was significantly lower in methotrexate than the leflunomide group side effects: No Table 1. Demographic and Clinical Characteristics Among Study Groups Variables Methotrexate Group (n=20) Leflunomide Group (n=20) P value Sex (N, %) Male Female 11 (55.0%) 9 (45.0%) 14 (70.0%) 6 (30.0%) 0.327 Age (years) Mean±SD 38.9 ± 12.88 37.6 ± 13.6 0.758 Range (Min. – Max.) 42 (18 - 60) 33 (26 - 59) Occupation (N, %) Housewife 4 (20%) 6 (30%) 0.902 Employee 8 (40%) 7 (35%) Student 3 (15%) 3 (15%) Other 5 (25%) 4 (20%) Economic status (n, %) High 2 (10%) 2 (10%) 0.891 Intermediate 16 (80%) 15 (75%) Low 2 (10%) 3 (15%) FH of psoriasis 2 (10%) 3 (15%) 0.663 Duration of the disease Mean±SD 11.2 ± 8.69 10.75 ± 8.06 0.866 Range (Min. – Max.) 28 (2 - 30) 27 (3 - 30) FH = positive family history…; SD = standard deviation. 4 Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 Figure 1. Male patient, 60 years old, with psoriasis vulgaris his Psoriasis Area Severity Index (A) before metotrexate was 34.1 that decreased to 0 (B) after 12 weeks of treatment. Figure 2. Male patient, 55 years old, with psoriasis vulgaris his Psoriasis Area Severity Index (A) before metotrexate was 43.1 that decreased to 0 (B) after 12 weeks of treatment. Figure 3. Male patient, 40 years old, with psoriasis vulgaris his Psoriasis Area Severity Index (A) before metotrexate was 34.2 that decreased to 2.3 (B) after 12 weeks of treatment. Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 5 Figure 4. Female patient 60 years old with psoriasis vulgaris her Psoriasis Area Severity Index (A) before oral leflunomide was 36.3 that decreased to 2.5 (B) after 12 weeks of treatment. Figure 5. Male patient 27 years old with psoriasis vulgaris his Pso- riasis Area Severity Index (A) before oral leflunomide was 21.6 that decreased to 2.4 (B) after 12 weeks of treatment. significant difference was found between both groups in any of the reported side effects. None of the patients among both groups discontinued the treatment because of the side effects, nausea and vomit- ing were the most frequent side effect among patients within the leflunamide group, this was similar to the methotrex- ate group (P = 677 and 465 respectively). Gastrointestinal manifestation, general and dermatological side effects were comparable between both groups (Table 2). Conclusions Methotrexate has been the treatment of choice for severe psoriasis for decades the main objective of the current study was to compare the efficacy and safety of the anti-arthritic medication leflunamide versus methotrexate in treating moderate to severe cases with psoriasis [16]. Leflunomide, a disease-modifying antirheumatic drug, was initially licensed for the treatment of psoriatic arthritis. Patients treated with leflunamide for psoriatic arthritis showed promising short and long-term improvement of cutaneous psoriasis lesions suggesting that it can be a good potential for treating pso- riasis [17]. Our results were in accordance with previous double blinded trials studied leflunomide as a monotherapy for pso- riasis compared to placebo [18-20]. Compared to placebo; these studies showed significant reduction of PASI among treated patients. We suggest that the effect of leflunomide on psoriasis could be attributed to prevention of pyrimidine synthesis pathway by inhibiting the enzyme dihydroorotate dehydrogenase On the other side, Thami and Garg included 10 pa- tients with different severity and types of psoriasis and showed no clinically significant improvement after 6 to 8 months of treatment with leflunomide, 20 mg/d [21]. In another study, 8 of 12 patients with psoriatic arthritis had moderate to marked clinical improvement in their pso- riasis after 2 to 3 months of treatment with leflunomide alone or in combination with another disease-modifying antirheumatic drug [20]. Other case-series of 8 patients receiving leflunomide, 20mg/d, over 12 weeks showed a reduction in PASI score and improvement in quality of life in 6 patients [19]. 6 Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 Figure 7. Female patient, 58 years old, with psoriasis vulgaris her Psoriasis Area Severity Index (A) before oral leflunomide was 25.2 that decreased to 2.4 (B) after 12 weeks of treatment. Figure 8. Female patient ,56 years old, with psoriasis vulgaris her Psoriasis Area Severity Index (A) before oral leflunomide was 25 that decreased to 0 (B) after 12 weeks of treatment. Figure 6. Male patient, 27 years old, with psoriasis vulgaris his Psoriasis Area Severity Index (A) before oral leflunomide was 59.92 that decreased to 2.2 (B) after 12 weeks of treatment. Original Article | Dermatol Pract Concept. 2024;14(3):e2024165 7 to moderate anemias, mild to moderate liver adverse events. However, chronic kidney injury did not differ between drugs. In addition, acute kidney injury, serious infections and major gastrointestinal adverse effects had no clinically significant difference between therapies. These results confirm the value of the current study, where leflunomide was associated with better profile of side effects regardless of the insignificant difference between groups. This could be explained by the small number of included subjects in each group. L Although our study had several methodological and scientific strengths as the double blinded design, the computer assisted randomization as well as the new research question compar- ing two medications that were not compared in psoriasis be- fore, it is still important to consider certain limitations when reading our results, we did not perform a sample size calcula- tion, we only could study a limited number of participants and we did not follow up for long term effects and recurrences. In conclusion, leflunamide is an anti-arthritic and low- cost drug that can effectively treat moderate to severe psori- asis as effective as MTX. References 1. Schwartzman M, Abutalib Z, Mandl LA. Current Medica- tion Practices and Preferences Among Patients With Psoriatic Arthritis. J Clin Rheumatol. 2022;28(2):55-61. DOI: 10.1097 /RHU.0000000000001799. PMID: 35192589. PMCID: PMC 8887780. 2. Walter K. Psoriasis. JAMA. 2022 May 17;327(19):1936. doi: 10.1001/jama.2022.5270. PMID: 35579640.. 3. 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